In 2004, it is expected that over 1.3 million new cancer cases will be diagnosed and an estimated 563,700 Americans will die of this disease. The overall goal of our NCDDG program is to discover marine natural product leads for cancer chemotherapy. There are five laboratory programs operating in a close and synergistic fashion as follows: Lab Program #1 at the Novartis Institutes of Biomedical Research, Inc. (NIBRI), led by Executive Director Dennis France;Lab Program #2 led by Prof. Phillip Crews (PI of this NCDDG), University of California, Santa Cruz (UCSC);Lab Program #3 led by Prof. William Gerwick, Oregon State University (OSU);Lab Program #4 led by Dr. Amy Wright, Harbor Branch Oceanographic Institution (HBOI);and Lab Program #5 led by Prof. William Fenical, Scripps Institution of Oceanography, University of California San Diego (SIO-UCSD). Our overall aims are as follows. (1) To employ the primary epigenetic and molecular screens at NIBRI to guide all phases of this research. (2) To utilize the academic programs to discover and characterize new, more effective anticancer drug leads from marine macro- and microorganisms. (3) To expand the collection of marine organisms to previously unexplored or underexplored ocean environments (e.g., deep water, new territories, new taxa) using the powerful combination of resources, experience, and equipment of the NCDDG collaborators. (4) To accelerate the discovery process by using biodiverse marine collections for the LC generation of chemodiverse peak libraries for evaluation in high throughput screens in parallel with spectroscopic evaluation. (5) To utilize state-of-the-art MS and NMR techniques for dereplication or structure elucidation. (6) To use medicinal chemical, chemoinformatic, and structural biological follow-up for lead optimization. (7) To conduct advanced preclinical evaluation to identify compounds with potential utility against important human solid tumors such as breast, colon, lung, ovarrian and prostate.